Estrogen provides many beneficial effects early in life by regulating normal tissue development and several physiological functions. While estrogen replacement therapy (ERT) in women was expected to reduce the health risks associated with the age-related decline in estrogen levels during menopause, ERT also resulted in increased progression to other types of diseases. Hence, distinguishing the signaling pathways that regulate the beneficial and detrimental effects of estrogen is important for developing interventions that selectively harness the hormone's beneficial effects, while minimizing its side effects. Estrogen can minimize mitochondrial dysfunction, which is thought to contribute to aging phenotypes. Decline in estrogen levels during menopause may lead to progressive mitochondrial dysfunction and may permanently alter cellular response, including that of estrogen (i.e., ERT). This review discusses the interplay between estrogen and mitochondrial function during the aging process and suggests a potential role of mitochondria in influencing the pleiotropic action of estrogen.